Using a Mouse Model, Researchers Now Understand Changes Occurring in the Brain Before the Onset of Huntington's Disease

New highly efficient DNA array technology brings researchers one step closer to understanding the progression of Huntington's disease and the potential for the development of therapies.

Huntington's disease affects nearly 30,000 people nationwide, with another 150,000 at risk for inheriting the disease. Like a genetic time bomb, one abnormal gene in Huntington's victims disrupts the brain's nerve cell functions, slowly degrading physical, intellectual and emotional capability and leading inevitably to death.

In a collaborative study conducted by the Fred Hutchinson Cancer Research Center (FHCRC) in Seattle and Massachusetts General Hospital (MGH) in Boston, researchers used a mouse model to identify changes that occur in nerve cells in the early stages of Huntington's disease. They identified several signaling molecules that could be targeted for future therapies. The results are reported in the May 22 issue of the journal Human Molecular Genetics.

Equally important to the knowledge gained is that the research team was able to do in six months what would have taken years in the past. Using new technologies in FHCRC's DNA Array Lab the team used genetic microchips--called microarrays--to survey the patterns of active and non-active genes at early and late symptomatic stages in a mouse model of Huntington's disease.

The research teams, led by Drs. Jim Olson, a pediatric oncologist at FHCRC, University of Washington and Children's Hospital and Regional Medical Center, and Ruth Luthi-Carter, a neurobiologist at MGH, monitored nearly 6,000 genes in the brain region most damaged by Huntington's disease. They found a small subset of genes to be affected by the disease, only two percent of the total. Importantly, many of the affected genes code the molecules that brain cells need to receive and process messages.

"The mouse models provide a window into the early stages of the disease," says Luthi-Carter. "This understanding may lead to therapeutic interventions that delay or prevent disease progression. One would

like to be able to stop the process at a point where most brain cells and functions remain intact, so that patients can continue to enjoy normal lives."

"In a matter of months we accomplished what would have taken years using previous technology, says Olson. "Technology developed by a company called Affymetrix enabled us to identify four potential strategies for treating this devastating disease. We are now testing candidate drugs in the mouse model to see whether the symptoms can be reduced or delayed."

Affymetrix's microarrays, called GeneChipsÒ , are manufactured onto silicon wafers employing many of the same technologies used to make computer chips. These wafers contain a dense grid of molecular bits of genes called probes. The role of these probes is to function like molecular Velcro by grabbing onto specific strands of RNA, the threadlike molecule that active genes produce. Probes within each grid locus on the wafer correspond to a single gene. As such, a single microarray can contain probes for thousands of genes. Researchers extract RNA from cells in a tissue sample, label it with a fluorescent dye, and inject it onto a GeneChipÒ . Each bit of RNA sloshes around until it comes in contact with a probe that matches it and grips it tightly. Some of the probes collect a lot of RNA while other areas collect very little. Using a computer-controlled laser to scan each quadrant on the grid, the location and intensity of light emitted by the dye indicates which genes are active and how active they are. To promote further studies using the powerful Affymetrix technology a consortium of over 50 scientists from leading laboratories has been established to rapidly assess genetic changes in Huntington's disease and other neurologic diseases.

Technology aside, the real story of Olson's interest in Huntington's disease began on the quiet shore of Lake Maracaibo in the northwest corner of Venezuela in San Luis, a fishing town much like any other Venezuelan village. Spend time in San Luis and something extraordinary becomes apparent. A noticeably large number of the people walk erratically, weaving down the streets, lurching and jerking with every step. There are more people in San Luis, and in associated areas around it, with Huntington's disease than anywhere else in the world.

"It is really a nasty disease because it deals a double emotional blow," says Olson, who first worked on Huntington's disease 15 years ago. "It strikes most Americans in midlife at about the time their children are entering middle school. Not only are they told they have the disease but also that they have possibly passed it on to their children."

Olson first visited San Luis in 1988as a graduate student in Dr. Anne Young's lab at the University of Michigan. "During my visits to Venezuela, I formed an emotional bond with these people," says Olson. "Even though I decided to go into pediatric oncology, I vowed that if I ever had the opportunity to do something for these people, I would."

Last January, the opportunity presented itself. On a visit with Young, now chief of neurology at MGH, Olson and his former mentor discussed a series of experiments she planned on Huntington's disease.

"The more we talked the more it seemed like a natural marriage of research approaches with the FHCRC's newly launched DNA Array Lab," Olson says.

Starting later that month, Olson and his collaborators in Young's lab began analyzing levels of gene activity in a mouse model of Huntington's disease.

"By April we confirmed that the mice had genetic changes similar to humans with Huntington's disease," Olson says. "And we also identified changes not previously associated with the disease. Understanding how nerve cells are damaged before symptoms occur is the first step toward developing therapies to forestall the onset of Huntington's disease."

The Fred Hutchinson Cancer Research Center is an independent, nonprofit research institution dedicated to the development and advancement of biomedical technology to eliminate cancer and other potentially fatal diseases. Recognized internationally for its pioneering work in bone-marrow transplantation, the Center's four scientific divisions collaborate to form a unique environment for conducting basic and applied science. The Hutchinson Center is the only National Cancer Institute-designated comprehensive cancer center in the Pacific Northwest. For more information, visit the Center's Web site at www.fhcrc.org.

The Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of almost $250 million and major research centers in AIDS, the neurosciences, cardiovascular research, cancer, cutaneous biology, transplantation biology and photomedicine. In 1994, the MGH joined with Brigham and Women's Hospital to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups and nonacute and home health services.

This research was supported by the Hereditary Disease Foundation, the Huntington's Disease Society of America, University of Washington Child Health Research Center, the Glendorn Foundation, W.M. Keck Foundation and the Burroughs Wellcome Fund.

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The Fred Hutchinson Cancer Research Center is an independent, nonprofit research institution dedicated to the development and advancement of biomedical technology to eliminate cancer and other potentially fatal diseases. Recognized internationally for its pioneering work in bone-marrow transplantation, the Center's four scientific divisions collaborate to form a unique environment for conducting basic and applied science. The Hutchinson Center is the only National Cancer Institute-designated comprehensive cancer center in the Pacific Northwest. For more information, visit the Center's Web site at <www.fhcrc.org>.

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